Compounds, compositions and methods

Abstract

Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.

1. At least one chemical entity chosen from compounds of Formula I 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein 
         T is —O—; 
         W, X, Y, and Z are —C═; 
         R 1  is selected from optionally substituted 
       
       
         
           
           
               
               
           
         
          optionally substituted 
       
       
         
           
           
               
               
           
         
          optionally substituted 
       
       
         
           
           
               
               
           
         
          and optionally substituted 
       
       
         
           
           
               
               
           
         
         R 2  is optionally substituted pyridin-3-yl; 
         R 3  is hydrogen; 
         R 4  is fluoro; 
         R 5  is hydrogen; 
         R 6  and R 7  are hydrogen; 
         R 13  is hydrogen. 
       
     
     
       2. At least one chemical entity of  claim 1  where R 1  is 
       
         
           
           
               
               
           
         
       
       each of which is substituted with one or more lower alkyl groups. 
     
     
       3. At least one chemical entity of  claim 2  where R 1  is 
       
         
           
           
               
               
           
         
       
     
     
       4. At least one chemical entity of  claim 1  wherein R 2  pyridin-3-yl optionally substituted with lower alkyl. 
     
     
       5. At least one chemical entity of  claim 1  wherein the compound of Formula I is chosen from yloxy))-5-fluorophenyl](3-pyridylamino)carboxamide;
 N-[3-((2S,7 a S)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizin-2-yloxy))-5-fluorophenyl](3-pyndylamino)carboxamide; 
 N-[3-((2Rg7 a R)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizin-2-yloxy))-5-fluorophenyl](3-pyridylamino)carboxamide; 
 N-[3-((7 a S,2R)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizin-2-yloxy))-5-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide; 
 N-[3-((1S,7 a R)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizinyloxy))-5-fluorophenyl](3-pyridylainino)carboxamide; 
 N-[3-((1S,7 a R)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizinyloxy))-5-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide; 
 N-[3-(2,6,-dimethyl-1,1-dioxo(1,2,6-thiadiazaperhydroin-4-yloxy))-5-fluorophenyl](3-pyridylamino)carboxamide; 
 N-[3-(2,6-dimethyl-1,1-dioxo(1,2,6-thiadiazaperhydroin-4-yloxy))-5-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide; 
 N-[3-((2R,7 a R)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizin-2-yloxy))-5-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide; 
 N-[3-((7 a S,2R)-6-methyl-5,5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizin-2-yloxy))-5-fluorophenyl]-N-hydroxy(3-pyridylamino)carboxamide; and 
 N-[3-((7 a S,2R)-6-methyl-5, 5-dioxo(2,3,6,7,7 a -pentahydro-5-thia-6-azapyrrolizin-2-yloxy))-5-fluorophenyl]-N-hydroxy[(6-methyl(3-pyridyl))amino]carboxamide. 
 
     
     
       6. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity of  claim 1 . 
     
     
       7. The pharmaceutical composition of  claim 6  wherein the composition is formulated in a form chosen from injectable fluids, aerosols, tablets, pills, capsules, syrups, creams, gels, and transdermal patches.